Asthma is a chronic inflammation disease characterized by reversible airway obstruction and non-specific bronchial hyperresponsiveness, and involves a complicated process of a series of inflammatory cells and inflammatory mediators. Common symptoms of an asthma patient are paroxysmal asthma, dyspnea, chest distress, or begma, and a few patients may have thoracodynia. At present, the asthma is a common disease and a frequently-occurring disease, which severely affects people's physical and psychological health.
The mechanism of airway obstruction in bronchial asthma (asthma) is related to bronchospasm caused by contraction of airway smooth muscle, mucous edema caused by vascular leakage, increased mucus secretion, and infiltration of inflammation cells induced by eosinophils, and a variety of inflammatory mediators, such as histamine, leukotrienes (LTs), thromboxane, prostaglandin, or the like, participate in an inflammation reaction of upper and lower airways. The asthma relates to a complicated process of a series of inflammatory cells and inflammatory meditors [British Medical Journal 1998, 316(15):1257-1258]. Researches show that leukotrienes plays an important role In the pathogenesis of asthma [Sampson A, Holgate S. Leukotriene modifiers in the treatment of asthma [J]. BMJ, 1998, 316(5): 1257-1258.], and plays an key role on the occurrence and development of the asthma. Therefore, the leukotriene receptor antagonist becomes the most effective mediator antagonist in clinic treatment of asthma, and uses of these drugs may accomplish an important breakout in asthma treatment.
In the later period of 1970s, cysteinyl leukotrienes (CysLT) is found to be an important mediator of asthma. The leukotrienes is generated by inflammatory cells such as mastocyte, oxyphil cell, or the like, and has multiple biological effects in the pathogenes is of asthma: increasing formation of vascular permeability and edema; increasing mucus production and reducing mucociliary transportation; attracting the inflammatory cells (such as eosinophils) to migrate from blood to the airway and release the inflammatory mediators, which may damage airway epithelium; and directly causing bronchospasm and stimulating the smooth muscle cell proliferation. The leukotrienes acts through the receptor thereof. The leukotriene receptors are distributed in all smooth muscle cells, dendritic cells, eosinophils, monocytes, macrophages, and B lymphocytes. An immunofluorescence detection shows that the CysLT1 receptors are distributed in both the smooth muscle of a central airway and a peripheral small airway in a lung tissue. The leukotriene receptor antagonist (LTRA) may improve aeration and relieve symptoms of asthma patient, which further proves the effect of the leukotrienes for asthma.
As gradually known effects of LTs in the bronchial hyperresponsiveness of asthma and confirmation of the LTs receptor sites, concerns have been raised about the situation the inhibitor sythesized by leukotriene receptor antagonist (LTRA) and LTs in prevention and treatment of asthma. The first leukotriene D4 (LTD4) receptor antagonist ibudilast (ibudilast, ketas) was applied in clinic in 1989. A new-generation LTRA zafirlukast (commercially named as encoreter) was marketed abroad as anti-asthmatic, anti-inflammatory and antiallergic drug in 1996, and had experienced certain clinic applications. Drugs with these LTs antagonism effects are a new trend to treat asthma at currently.
Mechanism of the leukotriene receptor antagonist (LTRAs) mainly lies in the following aspects: 1. Anti-inflammatory effect, preventing and relieving infiltration of inflammation cells. After taking zafirlukast or montelukast, as the improvement of lung function, lymphocyte counts, basophilic granulocyte counts, eosinophilic granulocyte counts, and scavenger cell counts in sputum, peripheral blood, and bronchoalveolar lavage fluid (BALF) of the patient are remarkably reduced, and the reduction degree is related to the improvement degree of vital capacity and daytime symptoms; 2. Relaxing the bronchial smooth muscle; 3. Suppressing bronchus contraction caused by sports. In asthma patients, the bronchus contraction caused by sports is about 70% to 80%, and LTRAs can significantly suppress the bronchus contraction caused by sports; and 4. Effects on aspirin intolerance asthma (AIA), wherein the patient suffering from aspirin intolerance asthma present characteristics of chronic rhinitis, repeatedly occurrence of nasal polyp, asthma, and intolerance of the drugs like aspirin, and this asthma is difficult to control by regular treatments, and the patients of this type are often accompanied with over-producing cysteinyl leukotrienes and up regulation of LTC 4 synzyme. Many researches verify that the LTC4 synzyme of bronchus biopsy tissue of AIA is over expressed accompanying with increasing cysteinyl leukotriene level in the bronchoalveolar lavage fluid when comparing the patient suffering the aspirin intolerance asthma with healthy persons.
LTRAs has good tolerance, and large-scale clinical experiments in recent years verify that compared with a placebo, the LTRAs has significant clinical therapeutic effects, and no apparent side effect have been found in long term usage and has good tolerance, which is also very effective and safe for children, and no occurrence of death and severe negative reactions have been reported.
The LTRAs available on the market currently and applied in clinic mainly includes Zafirlukast (Zafirlukast, , Acolate), Pranukast (Pranukast), and Montelukast (Montelukast, , Singulair). Wherein, Montelukast is a novel and powerful blocker drug of cysteinyl leukotriene receptor 1 (CysLTR.) with high selectivity and good tolerance developed in recent years, which can competitively antagonize the combination of leukotrienes D4 (LTD4) and Cys-LT1 receptor, thereby to suppress the activity of the leukotrienes, and reduce the expression of endothelium growth factor of blood vessel to adjust the permeability of the blood vessel, and improve the airway edema. The drug can effectively prevent and suppress the increase of vascular permeability, bronchospasm, and airway mucus hypersecretion caused by leukotrienes, and reduce the airway hyperresponsiveness, which has no apparent negative effects to important organs or systems, and has good compliance. As the inflammation mediator antagonist, its anti-asthmatic effect has been proved [Markham A, Faulds D. Montelukast [J]. Drugs, 1998, 56(2):251-7.]. The Montelukast is mainly used for prevention and long-term treatment of asthma of adult and child in clinic [LEE K S, KIM S R, PARK H S, et al. Cysteinyl leukotriene receptor antagonist regulates vascular permeability by reducing vascular endothelial growth factor expression [J]. Allergy Clin Immunol, 2004, 114(5): 1093-1099.]. A double-blind, random, crossed and antithetical clinical research shows that the Montelukast can significantly suppress bronchus contraction caused by inhaling LTD4 [De Lepeleire I, Reiss T F, Rochette F, et al. Montelukast causes prolonged, potent leukotriene D4-receptor antagonism in the airways of patients with asthma [J]. Clin Pharmacol Ther, 1997, 61(1): 83.]. The Montelukast may also suppress the bronchus contraction caused by movement, Bronsky E A, et al. [Bronsky E A, Kemp J P, Zhang J, et al”. Dose related protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval [J]. Clin Pharmacol Ther, 1997, 62(5):556.]. The suppression condition of the Montelukast to the bronchus contraction caused by sports is tested on the asthma patient.
Montelukast sodium (Singulair) is the first oral leukotriene receptor antagonist. The leukotriene is one of the important mediators in a series of inflammatory cells and inflammatory mediators in pothogenesy of the bronchial asthma, and plays a key role in generation and development of the bronchial asthma in the pathophysiology of the asthma.
Montelukast sodium (Montelukast, Singulair) is one unique high-selectivity leukotriene receptor antagonist in-taken once a day currently, and is suitable for treating asthma of adult and child, and syndrome of asthma and anaphylactic rhinitis asthma. Since the Montelukast has a relatively wide application range, and is convenient to intake, it has been widely recognized by clinician and used in clinic currently although manufacturing and application in clinic very late.
Recently, Adverse Events Reporting System (AERS) of Food and Drug Administration (FDA) has received many reports about side effects on neuropsychiatric aspect of anti-leukotriene drugs relating to the Montelukast (Singulair) or the like, and most reports are related to the Montelukast (Singulair) that may induce a suicide tendency. The drug is the most frequently-used anti-leukotriene prescription drug currently, and from clinical description of the suicide reports of some patients, the negative suicide events are actually caused by the drugs. Food and Drug Administration (FDA) sent an announce to medical workers and patients on Mar. 27, 2008 [Announcement 03/27/2008], and considered that the use of the Singulair may possible to cause changes of behavior/emotion and suicide tendency and behavior. The patient transitorily does not need withdrawal, but clinical doctors should closely monitor whether the patients taking these drugs present changes of behavior/emotion, and whether the patients develop suicide tendency and behavior. For the children taking Montelukast (Singulair), it should be pay attention to these children whether present appearances of hyperactivity, attention deficit, aggressive behavior, lethargy, depression, etc.
In 2009, after investigations, FDA officially informed that three asthma drugs including Montelukast (Singulair) have a possibility to cause mental-health problems, and manufacturers of anti-leukotriene drugs should mark drug-induced risks on drug label. FDA issued a declaration on its website to indicate that some asthma patients taking Montelukast (Singulair), Accolte, and Zileuton appear side effects of depressive illness, anxiety, suicide tendency, etc. This FDA investigation verifies that three asthma drugs including Montelukast (Singulair) have a possibility to cause mental-health problems. FDA stated that both clinical doctors and asthma patients should clearly know potential risks of these drugs to the mental health.
A spokesman from Merck Corporation which is a manufacturer of Montelukast (Singulair) stated that the risk of neuropsychiatric side effects has been noted in the “negative reaction” part of the instructions of Montelukast (Singulair), and it will be described in the part of matters needing attention of the drug in future.
The prior art has described some quinoline-containing compounds served as antagonist and having active effects to leukotrienes.
For example, EP318, 093 (Merck) and CN1061407A (Merck Frosst Canada Inc.) describe a compound having structure A. A compound having a structural formula B has been disclosed in WO89/12629 (Rorer) and US005565473A.
